Generalized immune activation and apoptosis are key characteristics of progressive HIV-1 disease. HIV-1 Tat protein has been linked to skewing of naive T-cell differentiation and apoptosis;however, the exact mechanisms are not clearly defined. The GLI transcription factors are important regulatory proteins that are involved in cellular differentiation, proliferation, apoptosis, and gene transcription. We have discovered putative GLI binding sites in several pro-inflammatory and pro-apoptotic genes. Our proposal focuses on Tbx21 (Tbet) and TGF-21. Based on these data our overall hypothesis is that HIV-1 infection induces GLI protein activation to turn on immune specific genes that induce generalized immune activation and subsequent apoptosis. Furthermore, we hypothesize that HIV-1 Tat induces TGF-21 transcription by binding to GLI2 at the TGF-21 promoter. The goal of this proposal is to further elucidate the mechanisms whereby HIV-1 activates the human GLI transcription factors to induce transcription of genes responsible for immune activation and apoptosis. Specifically, we intend: 1. To elucidate the mechanisms by which HIV-1 modulates Gli transcription factors to induce Tbx21 (Tbet) gene leading to a pro-inflammatory Th1 response. 2. To investigate how HIV-1 Tat interacts with the cellular transcription factors GLI2/3 to induce the pleiotropic cytokine TGF-21, which can skew CD4+ T-cell differentiation and/or apoptosis. The answers to these questions will undoubtedly lead to increased knowledge of viral pathogenesis and general immunology. These unknown pathways would also be worthwhile therapeutic targets to disable the virus'ability to induce generalized immune activation and bystander apoptosis. The implications of understanding how TGF-21 is transcriptionally regulated are not exclusively pertinent to HIV-1 disease. This pleiotropic immunosuppressive and pro-apoptotic cytokine has key roles in other infectious diseases, autoimmunity, and cancer (HTLV-I, multiple sclerosis, gliomas, etc.). PUBLIC HEALTH RELEVANCE: Immune suppression is a key characteristic of progressive HIV-1 disease. The persistent down-regulation of antiviral cell-mediated responses and increase of immunoregulatory T-cells during chronic HIV infection disables the immune system's control over viral replication as well as opportunistic infections. The viral proteins HIV gp120 and Tat have been attributed to this immunosuppression, but the underlying mechanisms have not been clearly defined. We have recently found that the glioma (Gli) transcription factors are important in the induction the Tbet protein which is essential in cell-mediated immune response, and that HIV-1 inhibits Gli activity. The goal of this proposal is to further elucidate the mechanisms whereby HIV-1 modulates the human Gli transcription factors to skew T-cell differentiation away from antiviral Th1 cells toward immunosuppressive T-cells. The answers to these questions will undoubtedly lead to increased knowledge of viral pathogenesis and general immunology.